The Fabry Disease disease mechanism overview
Fabry disease is a rare, inherited disorder that falls under the category of lysosomal storage diseases. Its root cause lies in a genetic mutation affecting the body’s ability to break down a specific type of fat called globotriaosylceramide (Gb3 or GL-3). This malfunction results in the accumulation of Gb3 within various cells, leading to a cascade of damaging effects throughout the body.
The core of Fabry disease’s mechanism is a deficiency or malfunction of the enzyme alpha-galactosidase A (α-Gal A). Normally, this enzyme resides within lysosomes—cellular organelles responsible for digesting and recycling various biomolecules. α-Gal A’s primary role is to cleave and break down Gb3, preventing its buildup within cells. When the enzyme is deficient or dysfunctional, Gb3 begins to accumulate progressively within the lysosomes of multiple cell types, including those in blood vessels, kidneys, heart, skin, and nervous tissue.
This accumulation disrupts normal cellular function on several levels. In blood vessel walls, Gb3 deposits cause thickening and stiffening of the vascular tissue, leading to impaired blood flow and increased risk of cardiovascular complications. In the kidneys, Gb3 buildup damages glomeruli and tubules, potentially leading to progressive renal failure. Similarly, in the heart, it can cause hypertrophy and fibrosis, contributing to cardiac problems such as arrhythmias and heart failure. The nervous system may also be affected, resulting in pain, numbness, and other neurological symptoms.
The genetic aspect of Fabry disease is autosomal recessive, which means a person must inherit two defective copies of the GLA gene—one from each parent—to manifest the disease. Carriers, with only one mutated gene, typically do not show symptoms but can pass the mutation to their offspring. The GLA gene encodes the α-Gal A enzyme, and mutations in this gene can vary widely, from small deletions or insertions to missense mutations, all affecting enzyme activity to different degrees.
The pathophysiology of Fabry disease is not solely due to Gb3 accumulation; secondary effects also play a role. The storage material can induce oxidative stress, inflammation, and cellular apoptosis, further exacerbating tissue damage. Over time, these cellular changes translate into the clinical manifestations of the disease, which include painful neuropathy, skin lesions called angiokeratomas, hypohidrosis, and severe organ involvement.
Understanding the disease mechanism has been pivotal in developing targeted therapies. Enzyme replacement therapy (ERT) aims to supplement the deficient α-Gal A enzyme, helping to reduce Gb3 buildup. More recently, pharmacological chaperones that stabilize specific enzyme mutations and gene therapy approaches have been explored to address the root cause of the deficiency.
In summary, Fabry disease is fundamentally caused by a genetic defect leading to enzyme deficiency, which results in the harmful accumulation of Gb3 within cells. This build-up triggers widespread cellular and tissue damage, manifesting in diverse and progressive clinical symptoms. Advances in understanding its mechanism continue to inform targeted treatments, offering hope for improved management and quality of life for those affected.
